Project 3 Summary Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease with no effective therapy. Lack of efficacy of current therapies may result from poor choices of therapeutic targets/drugs as well as poor penetration of systemic therapies that currently rely on passive transport across the restrictive endothelial cell (EC) barrier leading to insufficient drug concentrations inside diseased lung tissue. Dose escalations become limited by systemic side effects. Compounds targeting TGF pro-fibrogenic effects show promise but can have unintended systemic effects/toxicity. The goal of this innovative translational project is to create novel, more effective IPF therapies by rapidly and specifically pumping therapeutic agents that inhibit TGF signaling into fibrotic lung tissue. We have discovered antibodies (Abs) that are pumped specifically into lung tissue within minutes of intravenous injection and exceed passive lung delivery by >100-fold, thus creating an unprecedented lung delivery system based on the ability of lung endothelial caveolae to rapidly, actively, and specifically traffic targeted Abs across the EC barrier and to concentrate them and any attached cargo inside lung tissue. We will determine the ability of this transvascular pumping system to deliver key, well-studied inhibitors of the TGF pathway into the lung to reach their intended targets. As a prerequisite to rapid clinical translation, we will compare efficacy of caveolae-targeted therapies to the original therapies in complementary preclinical rodent models. Our innovative approach will be tested in the following specific aims: 1) To study the ability of lung caveolae-targeting antibody to specifically and rapidly deliver therapeutic inhibitors of the TGF fibrogenic pathway into fibrotic lungs of rodents; 2) To evaluate the ability of lung caveolae-targeting antibody to enhance the efficacy of specific therapeutic agents in blocking the function, signaling and potent fibrogenic effects of TGF in vivo and in treating pulmonary fibrosis; and 3) To utilize human clinical samples from patients with IPF to evaluate tissue processing and targeting of our most effective therapeutic agents. We expect to inhibit key fibrogenic pathways in vivo, improve overall therapeutic efficacy and decrease toxicity, thereby creating new promising IPF therapies for clinical testing.